(1) Field of the Invention
The present invention relates to compositions comprising matrix metalloproteinase 11 (MMP-11) or stromelysin-3 (ST-3) or the nucleic acid encoding the MMP-11 for use in vaccines for treating tumors and cancers, which overexpress MMP-11. In particular embodiments, the compositions comprise a nucleic acid encoding a fusion polypeptide that includes a catalytically inactivated MMP-11 linked at the C-terminus to an immunoenhancing element wherein the codons encoding the MMP-11 and the immunoenhancing element have been optimized for enhanced expression of the fusion polypeptide in human cells. In other embodiments, the compositions comprise the catalytically inactivated MMP-11 linked at the C-terminus to an immunoenhancing element. The compositions can be used alone or in synergy with vaccines against other tumor associated antigens as well as with conventional therapies such as radiation therapy and chemotherapy.
(2) Description of Related Art
Matrix Metalloproteinase-11 (MMP-11) or stromelysin 3 (ST3) is expressed in many, if not most, invasive primary carcinomas and in a number of their metastases and more rarely in sarcomas and other non-epithelial malignancies (See Basset et al., Critical Reviews in Oncology/Hematology 26: 43-53, (1997)). Measuring levels of MMP-11 expression can be used to identify patients at greatest risk for cancer recurrence. It has been shown that recurrent breast carcinomas occurred more frequently in patients who had high levels of MMP-11 RNA or protein in their tumors than in patients who had low levels of MMP-11 RNA or protein in their tumors. Similarly, MMP-11 expression was found to be increased in pancreatic tumors as compared to normal tissue and the level of MMP-11 expression was strongly associated with lymph node involvement and overall survival (Jones et al., Clin. Cancer Res. 10: 2832-2845, (2004)). MMP-11 mRNA expression is also significantly increased in colon carcinomas compared to MMP-11 mRNA expression in non-tumorous tissue (Thewes et al., Diagn. Mol. Pathol. 5: 284-290, (1996)).
The role of MMP-11 in cancer progression has been demonstrated by several pre-clinical observations. For example, MMP-11 expression was shown to promote tumor take in mice (Noel et al., J Clin Invest 97: 1924-1930 (1996)). MMP-11 was also shown to promote homing of malignant epithelial cells in a paracrine manner and the homing appears to require extracellular matrix associated factors (Masson et al., J. Cell Biol. 140: 1535-1541 (1998)) such as basic fibroblast growth factor (bFGF) (Mari et al., J. Biol. Chem. 273: 618-626 (1998)). MMP-11 protease activity can modulate cancer progression by remodeling extracellular matrix and inducing it to release microenvironmental factors (Noel et al., Oncogene 19: 1605-1612 (2000)). MMP-11 has been shown to have an anti-apoptotic and anti-necrotic effect on tumorous cells (Boulay et al., Cancer Res. 61: 2189-2193 (2001)), which appears to be mediated by its catalytic activity (Wu et al., J. Cell Biochem. 82:549-555 (2001)). MMP-11 deficiency has been shown to increase tumor free survival and modulate local or distant invasion (Andarawewa et al., Cancer Res. 63:5844-5849 (2003)). Knocking down MMP-11 mRNA in gastric cancer cells appears to dramatically suppresses tumor growth both in vitro and in vivo (Deng et al., Biochem. Biophys. Res. Comm. 26: 274-281 (2005)). MMP-11 has also been shown to interfere with the immune system's response against tumors in that a cleavage product of a1-proteinase inhibitor, generated by MMP-11 cleavage, decreases the sensitivity of tumor cells to natural killer cells (NK) (Kataoka et al., Am. J. Pathol. 154: 457-468, (1999)). In addition, an increased number of neutrophils and macrophages infiltrate tumors in MMP-11-null mice compared with wild-type mice, indicating that MMP-11 inhibits a chemoattractant for these cells (Boulay et al., Cancer Res. 61: 2189-2193 (2001)). Thus, MMP-11 appears to play a crucial role in the initial stage of tumorigenesis.
Several agents have been developed that block the synthesis of MMPs, prevent them from interacting with the molecules that direct their activities to the cell surface, or inhibit their enzymatic activity (reviewed in Egeblad and Werb, Nature Reviews 2: 163-174 (2002)). Most of agents were not specifically directed against MMP-11 but interfered with functions of other members of MMP family. However, clinical trials with several of these MMP inhibitors have suggested the inhibitors have a limited antitumor effect. Therefore, in light of the above, there is a need for anti-cancer therapies and treatments that inhibit or interfere with MMP-11 activity.